Method of treating certain cancers using an estrogen agonist/antagonist

ABSTRACT

The present invention provides methods of treating cancer of the liver, ovarian cancer, a desmoid tumor, glioma, pancreatic cancer, or renal cell carcinoma using an estrogen agonist/antagonist. The present invention also provides kits that contain an estrogen agonist/antagonist for treating cancer of the liver, ovarian cancer, a desmoid tumor, glioma, pancreatic cancer, or renal cell carcinoma.

CROSS REFERENCE TO RELATED APPLICATION This application claims priorityfrom of U.S. provisional application No. 60/264,566, filed Jan. 26,2001. FIELD OF THE INVENTION

[0001] The present invention provides methods of treating cancer of theliver, ovarian cancer, a desmoid tumor, glioma, pancreatic cancer, orrenal cell carcinoma that comprise administering to a patient havingcancer of the liver, ovarian cancer, a desmoid tumor, glioma, pancreaticcancer, or renal cell carcinoma a therapeutically effective amount of anestrogen agonist/antagonist. The present invention also provides kitsfor treating cancer of the liver, ovarian cancer, a desmoid tumor,glioma, pancreatic cancer, or renal cell carcinoma that comprises apharmaceutical composition comprising an estrogen agonist/antagonist andinstructions for administering the pharmaceutical composition to treatcancer of the liver, ovarian cancer, a desmoid tumor, glioma, pancreaticcancer, or renal cell carcinoma.

BACKGROUND OF THE INVENTION

[0002] Cancer is still one of the most dreaded diseases, and much effortand money has been spent trying to discover ways to treat cancer. Thepresent invention provides methods of treating certain cancers, namelycancer of the liver, ovarian cancer, a desmoid tumor, glioma, pancreaticcancer, or renal cell carcinoma.

[0003] There are two main types of cancer of the liver. The first typeis the result of metastasis of cancer from another area in the body. Inthis type of liver cancer, a cancer cell from another part of the bodymigrates to the liver and begins growth and tumor formation there.Commonly, the cancer cells that metastasize to the liver come fromcancer in the lungs, breast, colon, pancreas or stomach.

[0004] The second general type of liver cancer has been called primaryliver cancer. This type is composed of subtypes of cancers such ashepatocelluar carcinoma, which is the most common type of liver cancer,fibrolamellar carcinoma, cholangiocarcinoma, hepatoblastoma andangiosarcoma.

[0005] Ovarvian cancer is the second most commonly diagnosed and mostdeadly gynecologic malignancy. Ovarian cancer affects predominantlyperimenopausal and postmenopausal women.

[0006] Desmoid tumors, also called aggressive fibromatosis, are denseconnective tissue tumors.

[0007] Glioma is a type of brain tumor, which accounts for 45% ofintracranial tumors.

[0008] Pancreatic cancer has several varieties including ductaladenocarcinoma, cystadenocarcinoma, intraductal papillary-mucinoustumors, insulinoma, Zollinger-Ellison Syndrome (also known asgastrinoma), vipoma and glucagonoma.

[0009] Renal cell carcinoma accounts for about two percent of cancers.

[0010] The cancers listed above can all be treated by administering to apatient suffering therefrom a therapeutically effective amount of anestrogen agonist/antagonist.

[0011] The use of tamoxifen to treat ovarian cancer, heptaocellularcarcinoma, desmoid tumors, malignant gliomas, carcinoma of the pancreasand melanoma is discussed in Gelman, Edward P., Tamoxifen for theTreatment of Malignancies Other Than Breast and Endometrial Carcinoma,Seminars in Oncology, Vol. 24, No. 1, Suppl I (February), 1997, ppSI-65-SI 70.

SUMMARY OF THE INVENTION

[0012] The present invention provides methods of treating cancer of theliver, ovarian cancer, a desmoid tumor, glioma, pancreatic cancer, orrenal cell carcinoma, the methods comprising the step of administeringto a patient having cancer of the liver, ovarian cancer, a desmoidtumor, glioma, pancreatic cancer, or renal cell carcinoma atherapeutically effective amount of an estrogen agonist/antagonist.

[0013] In a preferred embodiment of the methods, the estrogenagonist/antagonist is a compound of formula (I):

[0014] wherein:

[0015] A is selected from CH₂ and NR;

[0016] B, D and E are independently selected from CH and N;

[0017] Y is

[0018] (a) phenyl, optionally substituted with 1-3 substituentsindependently selected from R⁴;

[0019] (b) naphthyl, optionally substituted with 1-3 substituentsindependently selected from R⁴;

[0020] (c) C₃-C₈ cycloalkyl, optionally substituted with 1-2substituents independently selected from R⁴;

[0021] (d) C₃-C₈ cycloalkenyl, optionally substituted with 1-2substituents independently selected from R⁴;

[0022] (e) a five membered heterocycle containing up to two heteroatomsselected from the group consisting of —O—, —NR²— and —S(O)_(n)—,optionally substituted with 1-3 substituents independently selected fromR⁴;

[0023] (f) a six membered heterocycle containing up to two heteroatomsselected from the group consisting of —O—, —NR²— and —S(O)_(n)—optionally substituted with 1-3 substituents independently selected fromR⁴; or

[0024] (g) a bicyclic ring system consisting of a five or six memberedheterocyclic ring fused to a phenyl ring, said heterocyclic ringcontaining up to two heteroatoms selected from the group consisting of—O—, —NR²— and —S(O)_(n)—, optionally substituted with 1-3 substituentsindependently selected from R⁴;

[0025] Z¹ is

[0026] (a) —(CH₂)_(p) W(CH₂)_(q)—;

[0027] (b) —O(CH₂)_(p) CR⁵R⁶—;

[0028] (c) —O(CH₂)_(p)W(CH₂)_(q)—;

[0029] (d) —OCHR²CHR³—; or

[0030] (e) —SCHR²CHR³—;

[0031] G is

[0032] (a) —NR⁷R⁸;

[0033] wherein n is 0, 1 or 2; m is 1, 2 or 3; Z² is —NH—, —O—, —S—, or—CH₂—; optionally fused on adjacent carbon atoms with one or two phenylrings and, optionally independently substituted on carbon with one tothree substituents and, optionally, independently on nitrogen with achemically suitable substituent selected from R⁴; or

[0034] (c) a bicyclic amine containing five to twelve carbon atoms,either bridged or fused and optionally substituted with 1-3 substituentsindependently selected from R⁴; or

[0035] Z¹ and G in combination may be

[0036] W is

[0037] (a) —CH₂—;

[0038] (b) —CH═CH—;

[0039] (c) —O—;

[0040] (d) —NR²;

[0041] (e) —S(O)_(n)—;

[0042] (g) —CR²(OH)—;

[0043] (h) —CONR²;

[0044] (i) —NR²CO—;

[0045] (k) —C≡C—;

[0046] R is hydrogen or C₁-C₆ alkyl;

[0047] R² and R³ are independently

[0048] (a) hydrogen; or

[0049] (b) C₁-C₄ alkyl;

[0050] R⁴ is

[0051] (a) hydrogen;

[0052] (b) halogen;

[0053] (c) C₁-C₆ alkyl;

[0054] (d) C₁-C₄ alkoxy;

[0055] (e) C₁-C₄ acyloxy;

[0056] (f) C₁-C₄ alkylthio;

[0057] (g) C₁-C₄ alkylsulfinyl;

[0058] (h) C₁-C₄ alkylsulfonyl;

[0059] (i) hydroxy (C₁-C₄)alkyl;

[0060] (j) aryl (C₁-C₄)alkyl;

[0061] (k) —CO₂H;

[0062] (l) —CN;

[0063] (m) —CONHOR;

[0064] (n) —SO₂NHR;

[0065] (O)—NH₂;

[0066] (p) C₁-C₄ alkylamino;

[0067] (q) C₁-C₄ dialkylamino;

[0068] (r) —NHSO₂R;

[0069] (s) —NO₂;

[0070] (t) -aryl; or

[0071] (u) —OH;

[0072] R⁵ and R⁶ are independently C₁-C₈ alkyl or together form a C₃-C₁₀carbocyclic ring;

[0073] R⁷ and R⁸ are independently

[0074] (a) phenyl;

[0075] (b) a C₃-C₁₀ carbocyclic ring, saturated or unsaturated;

[0076] (c) a C₃-C₁₀ heterocyclic ring containing up to two heteroatoms,selected from —O—, —N— and —S—;

[0077] (d) H;

[0078] (e) C₁-C₆ alkyl; or

[0079] (f) form a 3 to 8 membered nitrogen containing ring with R⁵ orR⁶;

[0080] R⁷ and R⁸ in either linear or ring form may optionally besubstituted with up to three substituents independently selected fromC₁-C₆ alkyl, halogen, alkoxy, hydroxy and carboxy;

[0081] a ring formed by R⁷ and R⁸ may be optionally fused to a phenylring;

[0082] e is 0, 1 or 2;

[0083] m is 1, 2 or 3;

[0084] n is 0, 1 or 2;

[0085] p is 0, 1, 2 or 3;

[0086] q is 0, 1, 2 or 3;

[0087] or an optical or geometric isomer thereof; or a pharmaceuticallyacceptable salt, N-oxide, ester, quaternary ammonium salt or prodrugthereof.

[0088] In another preferred embodiment of the methods, the estrogenagonist/antagonist is a compound of formula (IA)

[0089] wherein G is

[0090] R⁴ is H, OH, F, or Cl; and B and E are independently selectedfrom CH and N or an optical or geometric isomer thereof; or apharmaceutically acceptable salt, N-oxide, ester, quaternary ammoniumsalt, or a prodrug thereof.

[0091] In another preferred embodiment of the methods, the estrogenagonist/antagonist is(−)-cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-olor an optical or geometric isomer thereof; a pharmaceutically acceptablesalt, N-oxide, ester, quaternary ammonium salt, or a prodrug thereof.

[0092] In another preferred embodiment of the methods, the estrogenagonist/antagonist is(−)-cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol,D-tartrate salt.

[0093] In another preferred embodiment of the methods, the estrogenagonist/antagonist is 4-hydroxy tamoxifen, droloxifene, toremifene,centchroman, idoxifene, raloxifene,6-(4-hydroxy-phenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-naphthalen-2-ol,{4-[2-(2-aza-bicyclo[2.2.1]hept-2-yl)-ethoxy]-phenyl}-[6-hydroxy-2-(4-hydroxy-phenyl)-benzo[b]thiophen-3-yl]-methanone,EM-652, EM-800, GW 5638, GW 7604, or an optical or geometric isomerthereof; pharmaceutically acceptable salt, N-oxide, ester, quaternaryammonium salt, or prodrug thereof.

[0094] In another preferred embodiment of the methods, the estrogenagonist/antagonist is a compound of formula V or VI:

[0095] wherein:

[0096] R_(1B) is selected from H, OH, —O—C(O)—C₁-C₁₂ alkyl (straightchain or branched), —O—C₁-C₁₂ alkyl (straight chain or branched orcyclic), or halogens or C₁-C₄ halogenated ethers;

[0097] R_(2B), R_(3B), R_(4B), R_(5B), and R_(6B) are independentlyselected from H, OH, —O—C(O)—C₁-C₁₂ (straight chain or branched),—O—C₁-C₁₂ (straight chain or branched or cyclic), halogens, or C₁-C₄halogenated ethers, cyano, C₁-C₆ alkyl (straight chain or branched), ortrifluoromethyl;

[0098] X_(A) is selected from H, C₁-C₆ alkyl, cyano, nitro,trifluoromethyl, and halogen;

[0099] s is 2 or 3;

[0100] Y_(A) is the moiety:

[0101] wherein:

[0102] a) R_(7B) and R_(8B) are independently selected from the group ofH, C₁-C₆ alkyl, or phenyl optionally substituted by CN, C₁-C₆ alkyl(straight chain or branched), C₁-C₆ alkoxy (straight chain or branched),halogen, —OH, —CF₃, or —OCF₃; or

[0103] b) R_(7B) and R_(8B) are concatenated to form a five-memberedsaturated heterocycle containing one nitrogen heteroatom, theheterocycle being optionally substituted with 1-3 substituentsindependently selected from the group consisting of hydrogen, hydroxyl,halo, C₁-C₄ alkyl, trihalomethyl, C₁-C₄ alkoxy, trihalomethoxy, C₁-C₄acyloxy, C₁-C₄ alkylthio, C₁-C₄ alkylsulfinyl, C₁-C₄ alkylsulfonyl,hydroxy (C₁-C₄)alkyl, —CO₂H, —CN, —CONHR_(1B), —NH₂, —NH(C₁-C₄ alkyl),—N(C₁-C₄ alkyl)₂, —NHSO₂R_(1B), —NHCOR_(1B), —NO₂, or phenyl optionallysubstituted with 1-3 (C₁-C₄)alkyl; or

[0104] c) R_(7B) and R_(8B) are concatenated to form a six-memberedsaturated heterocycle containing one nitrogen heteroatom, theheterocycle being optionally substituted with 1-3 substituentsindependently selected from the group consisting of hydrogen, hydroxyl,halo, C₁-C₄ alkyl, trihalomethyl, C₁-C₄ alkoxy, trihalomethoxy, C₁-C₄acyloxy, C₁-C₄ alkylthio, C₁-C₄alkylsulfinyl, C₁-C₄ alkylsulfonyl,hydroxy (C₁-C₄)alkyl, —CO₂H, —CN, —CONHR_(1B), —NH₂, —NH(C₁-C₄ alkyl),—N(C₁-C₄ alkyl)₂, —NHSO₂R_(1B), —NHCOR_(1B), —NO₂, or phenyl optionallysubstituted with 1-3 (C₁-C₄)alkyl; or

[0105] d) R_(7B) and R_(8B) are concatenated to form a seven-memberedsaturated heterocycle containing one nitrogen heteroatom, theheterocycle being optionally substituted with 1-3 substituentsindependently selected from the group consisting of hydrogen, hydroxyl,halo, C₁-C₄ alkyl, trihalomethyl, C₁-C₄ alkoxy, trihalomethoxy, C₁-C₄acyloxy, C₁-C₄ alkylthio, C₁-C₄ alkylsulfinyl, C₁-C₄ alkylsulfonyl,hydroxy (C₁-C₄)alkyl, —CO₂H, —CN, —CONHR_(1B), —NH₂, —NH(C₁-C₄ alkyl),—N(C₁-C₄ alkyl)₂, —NHSO₂ R_(1B), —NHCOR_(1B), —NO₂, or phenyl optionallysubstituted with 1-3 (C₁-C₄)alkyl; or

[0106] e) R_(7B) and R_(8B) are concatenated to form an eight-memberedsaturated heterocycle containing one nitrogen heteroatom, theheterocycle being optionally substituted with 1-3 substituentsindependently selected from the group consisting of hydrogen, hydroxyl,halo, C₁-C₄ alkyl, trihalomethyl, C₁-C₄ alkoxy, trihalomethoxy, C₁-C₄acyloxy, C₁-C₄ alkylthio, C₁-C₄ alkylsulfinyl, C₁-C₄ alkylsulfonyl,hydroxy (C₁-C₄)alkyl, —CO₂H, —CN, —CONHR_(1B), —NH₂, —NH(C₁-C₄ alkyl),—N(C₁-C₄alkyl)₂, —NHSO₂R_(1B), —NHCOR_(1B), —NO₂, or phenyl optionallysubstituted with 1-3 (C₁-C₄)alkyl; or

[0107] f) R_(7B) and R_(8B) are concatenated to form a saturatedbicyclic heterocycle containing from 6-12 carbon atoms either bridged orfused and containing one nitrogen heteroatom, the heterocycle beingoptionally substituted with 1-3 substituents independently selected fromthe group consisting of hydrogen, hydroxyl, halo, C₁-C₄ alkyl,trihalomethyl, C₁-C₄ alkoxy, trihalomethoxy, C₁-C₄ acyloxy, C₁-C₄alkylthio, C₁-C₄ alkylsulfinyl, C₁-C₄ alkylsulfonyl, hydroxy(C₁-C₄)alkyl, —CO₂H, —CN, —CONHR_(1B), —NH₂, —NH(C₁-C₄ alkyl), —N(C₁-C₄alkyl)₂, —NHSO₂R_(1B), —NHCOR_(1B), —NO₂, or phenyl optionallysubstituted with 1-3 (C₁-C₄) alkyl; or an optical or geometric isomerthereof; or a pharmaceutically acceptable salt, N-oxide, ester,quaternary ammonium salt or prodrug thereof.

[0108] In another preferred embodiment of the methods, the estrogenagonist/antagonist is the compound of formula Va:

[0109] or an optical or geometric isomer thereof; or a pharmaceuticallyacceptable salt, N-oxide, ester, quaternary ammonium salt or prodrugthereof.

[0110] In another preferred embodiment of the methods, the estrogenagonist/antagonist is the compound of formula III (EM-652) or formula IV(EM-800) below:

[0111] or an optical or geometric isomer thereof; or a pharmaceuticallyacceptable salt, N-oxide, ester, quaternary ammonium salt or prodrugthereof.

[0112] Also provided by the present invention are kits for use by aconsumer to treat cancer of the liver, ovarian cancer, a desmoid tumor,glioma, pancreatic cancer, or renal cell carcinoma, the kits comprising:

[0113] (a) a pharmaceutical composition comprising an estrogenagonist/antagonist; and

[0114] (b) instructions describing a method of using the pharmaceuticalcomposition to treat cancer of the liver, ovarian cancer, a desmoidtumor, glioma, pancreatic cancer, or renal cell carcinoma.

[0115] In a preferred embodiment of the kits, the estrogenagonist/antagonist is a compound of formula (I):

[0116] wherein:

[0117] A is selected from CH₂ and NR;

[0118] B, D and E are independently selected from CH and N;

[0119] Y is

[0120] (a) phenyl, optionally substituted with 1-3 substituentsindependently selected from R⁴;

[0121] (b) naphthyl, optionally substituted with 1-3 substituentsindependently selected from R⁴;

[0122] (c) C₃-C₈ cycloalkyl, optionally substituted with 1-2substituents independently selected from R⁴;

[0123] (d) C₃-C₈ cycloalkenyl, optionally substituted with 1-2substituents independently selected from R⁴;

[0124] (e) a five membered heterocycle containing up to two heteroatomsselected from the group consisting of —O—, —NR²— and —S(O)_(n)—,optionally substituted with 1-3 substituents independently selected fromR⁴;

[0125] (f) a six membered heterocycle containing up to two heteroatomsselected from the group consisting of —O—, —NR²— and —S(O)_(n)—optionally substituted with 1-3 substituents independently selected fromR⁴; or

[0126] (g) a bicyclic ring system consisting of a five or six memberedheterocyclic ring fused to a phenyl ring, said heterocyclic ringcontaining up to two heteroatoms selected from the group consisting of—O—, —NR²— and —S(O)_(n)—, optionally substituted with 1-3 substituentsindependently selected from R⁴;

[0127] Z¹ is

[0128] (a) —(CH₂)_(p) W(CH₂)_(q)—;

[0129] (b) —O(CH₂)_(p) CR⁵R⁶—;

[0130] (c) —O(CH₂)_(p)W(CH₂)_(q)—;

[0131] (d) —OCHR²CHR³—; or

[0132] (e) —SCHR²CHR³;

[0133] G is

[0134] (a) —NR⁷R⁸;

[0135] wherein n is 0, 1 or 2; m is 1, 2 or 3; Z² is —NH—, —O—, —S—, or—CH₂—; optionally fused on adjacent carbon atoms with one or two phenylrings and, optionally independently substituted on carbon with one tothree substituents and, optionally, independently on nitrogen with achemically suitable substituent selected from R⁴; or

[0136] (c) a bicyclic amine containing five to twelve carbon atoms,either bridged or fused and optionally substituted with 1-3 substituentsindependently selected from R⁴; or

[0137] Z¹ and G in combination may be

[0138] W is

[0139] (a) —CH₂—;

[0140] (b) —CH═CH—;

[0141] (c) —O—;

[0142] (d) —NR²;

[0143] (e) —S(O)_(n)—;

[0144] (g) —CR²(OH)—;

[0145] (h) —CONR²;

[0146] (i) —NR²CO—;

[0147] (k) —C≡C—;

[0148] R is hydrogen or C₁-C₆ alkyl;

[0149] R² and R³ are independently

[0150] (a) hydrogen; or

[0151] (b) C₁-C₄ alkyl;

[0152] R⁴ is

[0153] (a) hydrogen;

[0154] (b) halogen;

[0155] (c) C₁-C₆ alkyl;

[0156] (d) C₁-C₄alkoxy;

[0157] (e) C₁-C₄ acyloxy;

[0158] (f) C₁-C₄ alkylthio;

[0159] (g) C₁-C₄ alkylsulfinyl;

[0160] (h) C₁-C₄ alkylsulfonyl;

[0161] (i) hydroxy (C₁-C₄)alkyl;

[0162] (j) aryl (C₁-C₄)alkyl;

[0163] (k) —CO₂H;

[0164] (l) —CN;

[0165] (m) —CONHOR;

[0166] (n) —SO₂NHR;

[0167] (o)—NH₂;

[0168] (p) C₁-C₄ alkylamino;

[0169] (q) C₁-C₄ dialkylamino;

[0170] (r) —NHSO₂R;

[0171] (s) —NO₂;

[0172] (t) -aryl; or

[0173] (u) —OH;

[0174] R⁵ and R⁶ are independently C₁-C₈ alkyl or together form a C₃-C₁₀carbocyclic ring;

[0175] R⁷ and R⁸ are independently

[0176] (a) phenyl;

[0177] (b) a C₃-C₁₀ carbocyclic ring, saturated or unsaturated;

[0178] (c) a C₃-C₁₀ heterocyclic ring containing up to two heteroatoms,selected from —O—, —N— and —S—;

[0179] (d) H;

[0180] (e) C₁-C₆ alkyl; or

[0181] (f) form a 3 to 8 membered nitrogen containing ring with R⁵ orR⁶;

[0182] R⁷ and R⁸ in either linear or ring form may optionally besubstituted with up to three substituents independently selected fromC₁-C₆ alkyl, halogen, alkoxy, hydroxy and carboxy;

[0183] a ring formed by R⁷ and R⁸ may be optionally fused to a phenylring;

[0184] e is 0, 1 or 2;

[0185] m is 1, 2 or 3;

[0186] n is 0, 1 or 2;

[0187] p is 0, 1, 2 or 3;

[0188] q is 0, 1, 2 or 3;

[0189] or an optical or geometric isomer thereof; or a pharmaceuticallyacceptable salt, N-oxide, ester, quaternary ammonium salt or prodrugthereof.

[0190] In another preferred embodiment of the kits, the estrogenagonist/antagonist is a compound of formula (IA):

[0191] wherein G is

[0192] R⁴ is H, OH, F, or Cl; and B and E are independently selectedfrom CH and N or an optical or geometric isomer thereof; or apharmaceutically acceptable salt, N-oxide, ester, quaternary ammoniumsalt, or a prodrug thereof.

[0193] In another preferred embodiment of the kits, the estrogenagonist/antagonist is(−)-cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-olor an optical or geometric isomer thereof; or a pharmaceuticallyacceptable salt, N-oxide, ester, quaternary ammonium salt, or a prodrugthereof.

[0194] In another preferred embodiment of the kits, the estrogenagonist/antagonist is(−)-cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol,D-tartrate salt.

[0195] In another preferred embodiment of the kits, the estrogenagonist/antagonist is 4-hydroxy tamoxifen, droloxifene, toremifene,centchroman, idoxifene, raloxifene,6-(4-hydroxy-phenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-naphthalen-2-ol,{4-[2-(2-aza-bicyclo[2.2.1]hept-2-yl)-ethoxy]-phenyl}-[6-hydroxy-2-(4-hydroxy-phenyl)-benzo[b]thiophen-3-yl]-methanone,EM-652, EM-800, GW 5638, GW 7604, or an optical or geometric isomerthereof; pharmaceutically acceptable salt, N-oxide, ester, quaternaryammonium salt, or prodrug thereof.

[0196] In another preferred embodiment of the kits, the estrogenagonist/antagonist is a compound of formula V or VI:

[0197] wherein:

[0198] R_(1B) is selected from H, OH, —O—C(O)—C₁-C₁₂ alkyl (straightchain or branched), —O—C₁-C₁₂ alkyl (straight chain or branched orcyclic), or halogens or C₁-C₄ halogenated ethers;

[0199] R_(2B), R_(3B), R_(4B), R_(5B), and R_(6B) are independentlyselected from H, OH, —O—C(O)—C₁-C₁₂ (straight chain or branched),—O—C₁-C₁₂ (straight chain or branched or cyclic), halogens, or C₁-C₄halogenated ethers, cyano, C₁-C₆ alkyl (straight chain or branched), ortrifluoromethyl;

[0200] X_(A) is selected from H, C₁-C₆ alkyl, cyano, nitro,trifluoromethyl, and halogen;

[0201] s is 2 or 3;

[0202] Y_(A) is the moiety:

[0203] wherein:

[0204] a) R_(7B) and R_(8B) are independently selected from the group ofH, C₁-C₆ alkyl, or phenyl optionally substituted by CN, C₁-C₆ alkyl(straight chain or branched), C₁-C₆ alkoxy (straight chain or branched),halogen, —OH, —CF₃, or —OCF₃; or

[0205] b) R_(7B) and R_(8B) are concatenated to form a five-memberedsaturated heterocycle containing one nitrogen heteroatom, theheterocycle being optionally substituted with 1-3 substituentsindependently selected from the group consisting of hydrogen, hydroxyl,halo, C₁-C₄ alkyl, trihalomethyl, C₁-C₄ alkoxy, trihalomethoxy, C₁-C₄acyloxy, C₁-C₄ alkylthio, C₁-C₄ alkylsulfinyl, C₁-C₄ alkylsulfonyl,hydroxy (C₁-C₄)alkyl, —CO₂H, —CN, —CONHR_(1B), —NH₂, —NH(C₁-C₄ alkyl),—N(C₁-C₄ alkyl)₂, —NHSO₂R_(1B), —NHCOR_(1B), —NO₂, or phenyl optionallysubstituted with 1-3 (C₁-C₄)alkyl; or

[0206] c) R_(7B) and R_(8B) are concatenated to form a six-memberedsaturated heterocycle containing one nitrogen heteroatom, theheterocycle being optionally substituted with 1-3 substituentsindependently selected from the group consisting of hydrogen, hydroxyl,halo, C₁-C₄ alkyl, trihalomethyl, C₁-C₄ alkoxy, trihalomethoxy, C₁-C₄acyloxy, C₁-C₄ alkylthio, C₁-C₄alkylsulfinyl, C₁-C₄ alkylsulfonyl,hydroxy (C₁-C₄)alkyl, —CO₂H, —CN, —CONHR_(1B), —NH₂, —NH(C₁-C₄ alkyl),—N(C₁-C₄ alkyl)₂, —NHSO₂R_(1B), —NHCOR_(1B), —NO₂, or phenyl optionallysubstituted with 1-3 (C₁-C₄)alkyl; or

[0207] d) R_(7B) and R_(8B) are concatenated to form a seven-memberedsaturated heterocycle containing one nitrogen heteroatom, theheterocycle being optionally substituted with 1-3 substituentsindependently selected from the group consisting of hydrogen, hydroxyl,halo, C₁-C₄ alkyl, trihalomethyl, C₁-C₄ alkoxy, trihalomethoxy, C₁-C₄acyloxy, C₁-C₄ alkylthio, C₁-C₄ alkylsulfinyl, C₁-C₄ alkylsulfonyl,hydroxy (C₁-C₄)alkyl, —CO₂H, —CN, —CONHR_(1B), —NH₂, —NH(C₁-C₄ alkyl),—N(C₁-C₄ alkyl)₂, —NHSO₂R_(1B), —NHCOR_(1B), —NO₂, or phenyl optionallysubstituted with 1-3 (C₁-C₄)alkyl; or

[0208] e) R_(7B) and R_(8B) are concatenated to form an eight-memberedsaturated heterocycle containing one nitrogen heteroatom, theheterocycle being optionally substituted with 1-3 substituentsindependently selected from the group consisting of hydrogen, hydroxyl,halo, C₁-C₄ alkyl, trihalomethyl, C₁-C₄ alkoxy, trihalomethoxy, C₁-C₄acyloxy, C₁-C₄ alkylthio, C₁-C₄ alkylsulfinyl, C₁-C₄ alkylsulfonyl,hydroxy (C₁-C₄)alkyl, —CO₂H, —CN, —CONHR_(1B), —NH₂, —NH(C₁-C₄ alkyl),—N(C₁-C₄ alkyl)₂, —NHSO₂R_(1B), —NHCOR_(1B), —NO₂, or phenyl optionallysubstituted with 1-3 (C₁-C₄)alkyl; or

[0209] f) R_(7B) and R_(8B) are concatenated to form a saturatedbicyclic heterocycle containing from 6-12 carbon atoms either bridged orfused and containing one nitrogen heteroatom, the heterocycle beingoptionally substituted with 1-3 substituents independently selected fromthe group consisting of hydrogen, hydroxyl, halo, C₁-C₄ alkyl,trihalomethyl, C₁-C₄ alkoxy, trihalomethoxy, C₁-C₄ acyloxy, C₁-C₄alkylthio, C₁-C₄ alkylsulfinyl, C₁-C₄ alkylsulfonyl, hydroxy(C₁-C₄)alkyl, —CO₂H, —CN, —CONHR_(1B), —NH₂, —NH(C₁-C₄ alkyl), —N(C₁-C₄alkyl)₂, —NHSO₂R_(1B), —NHCOR_(1B), —NO₂, or phenyl optionallysubstituted with 1-3 (C₁-C₄) alkyl; or an optical or geometric isomerthereof; or a pharmaceutically acceptable salt, N-oxide, ester,quaternary ammonium salt or prodrug thereof.

[0210] In another preferred embodiment of the kits, the estrogenagonist/antagonist is the compound of formula Va (TSE-424) below:

[0211] or an optical or geometric isomer thereof; or a pharmaceuticallyacceptable salt, N-oxide, ester, quaternary ammonium salt or prodrugthereof.

[0212] In another preferred embodiment of the kits, the estrogenagonist/antagonist is the compound of formula III (EM-652) or formula IV(EM-800) below:

[0213] or an optical or geometric isomer thereof; or a pharmaceuticallyacceptable salt, N-oxide, ester, quaternary ammonium salt or prodrugthereof.

[0214] In another preferred embodiment of the kits, the kits furthercomprise an additional compound that is useful to treat cancer of theliver, ovarian cancer, a desmoid tumor, glioma, pancreatic cancer, orrenal cell carcinoma.

DETAILED DESCRIPTION OF THE INVENTION

[0215] The present invention provides methods of treating cancer of theliver, ovarian cancer, a desmoid tumor, glioma, pancreatic cancer, orrenal cell carcinoma, the methods comprising the step of administeringto a patient having cancer of the liver, ovarian cancer, a desmoidtumor, glioma, pancreatic cancer, or renal cell carcinoma atherapeutically effective amount of an estrogen agonist/antagonist. Alsoprovided are kits for the treatment of cancer of the liver, ovariancancer, a desmoid tumor, glioma, pancreatic cancer, or renal cellcarcinoma, which kits comprise a pharmaceutical composition thatcontains an estrogen agonist/antagonist and instructions describingmethods of using the pharmaceutical composition to treat cancer of theliver, ovarian cancer, a desmoid tumor, glioma, pancreatic cancer, orrenal cell carcinoma.

[0216] The terms “treat”, “treatment”, and “treating” includepreventative (e.g., prophylactic) and palliative treatment or the act ofproviding preventative or palliative treatment.

[0217] The term “patient” means animals, particularly mammals. Preferredpatients are humans.

[0218] An “estrogen agonist/antagonist” is a compound that affects someof the same receptors that estrogen does, but not all, and in someinstances, it antagonizes or blocks estrogen. It is also known as a“selective estrogen receptor modulator” (SERM). Estrogenagonists/antagonists may also be referred to as antiestrogens althoughthey have some estrogenic activity at some estrogen receptors. Estrogenagonists/antagonists are therefore not what are commonly referred to as“pure antiestrogens”. Antiestrogens that can also act as agonists arereferred to as Type I antiestrogens. Type I antiestrogens activate theestrogen receptor to bind tightly in the nucleus for a prolonged time,but with impaired receptor replenishment (Clark, et al., Steroids1973;22:707, Capony et al., Mol Cell Endocrinol, 1975;3:233).

[0219] “A therapeutically effective amount” is an amount of an estrogenagonist/antagonist that when administered to a patient having cancer ofthe liver, ovarian cancer, a desmoid tumor, glioma, pancreatic cancer,or renal cell carcinoma provides for the treatment of one or moreconditions or symptoms of the cancer. Preferably, tumor size isdecreased upon administration of an estrogen agonist/antagonist.

[0220] The estrogen agonists/antagonists of the invention may beadministered systemically or locally. For systemic use, the estrogenagonists/antagonists herein are formulated for parenteral (e.g.,intravenous, subcutaneous, intramuscular, intraperitoneal, intranasal ortransdermal) or enteral (e.g., oral or rectal) delivery according toconventional methods. Intravenous administration can be by a series ofinjections or by continuous infusion over an extended period.Administration by injection or other routes of discretely spacedadministration can be performed at intervals ranging from weekly to onceto three or more times daily.

[0221] Preferred estrogen agonists/antagonists of the present inventioninclude the compounds described in U.S. Pat. No. 5,552,412. Thosecompounds are described by the formula designated herein as formula (I)given below:

[0222] wherein:

[0223] A is selected from CH₂ and NR;

[0224] B, D and E are independently selected from CH and N;

[0225] Y is

[0226] (a) phenyl, optionally substituted with 1-3 substituentsindependently selected from R⁴;

[0227] (b) naphthyl, optionally substituted with 1-3 substituentsindependently selected from R⁴;

[0228] (c) C₃-C₈ cycloalkyl, optionally substituted with 1-2substituents independently selected from R⁴;

[0229] (d) C₃-C₈ cycloalkenyl, optionally substituted with 1-2substituents independently selected from R⁴;

[0230] (e) a five membered heterocycle containing up to two heteroatomsselected from the group consisting of —O—, —NR²— and —S(O)_(n)—,optionally substituted with 1-3 substituents independently selected fromR⁴;

[0231] (f) a six membered heterocycle containing up to two heteroatomsselected from the group consisting of —O—, —NR²— and —S(O)_(n)—optionally substituted with 1-3 substituents independently selected fromR⁴; or

[0232] (g) a bicyclic ring system consisting of a five or six memberedheterocyclic ring fused to a phenyl ring, said heterocyclic ringcontaining up to two heteroatoms selected from the group consisting of—O—, —NR²— and —S(O)_(n)—, optionally substituted with 1-3 substituentsindependently selected from R⁴;

[0233] Z¹ is

[0234] (a) —(CH₂)_(p) W(CH₂)_(q)—;

[0235] (b) —O(CH₂)_(p) CR⁵R⁶—;

[0236] (c) —O(CH₂)_(p)W(CH₂)_(q)—;

[0237] (d) —OCHR²CHR³; or

[0238] (e) —SCHR²CHR³—;

[0239] G is

[0240] (a) —NR⁷R⁸;

[0241] wherein n is 0, 1 or 2; m is 1, 2 or 3; Z² is —NH—, —O—, —S—, or—CH₂—; optionally fused on adjacent carbon atoms with one or two phenylrings and, optionally independently substituted on carbon with one tothree substituents and, optionally, independently on nitrogen with achemically suitable substituent selected from R⁴; or

[0242] (c) a bicyclic amine containing five to twelve carbon atoms,either bridged or fused and optionally substituted with 1-3 substituentsindependently selected from R⁴; or

[0243] Z¹ and G in combination may be

[0244] W is

[0245] (a) —CH₂—;

[0246] (b) —CH═CH—;

[0247] (c) —O—;

[0248] (d) —NR²—;

[0249] (e) —S(O)_(n)—;

[0250] (g) —CR²(OH)—;

[0251] (h) —CONR²—;

[0252] (i) —NR²CO—;

[0253] (k) —C≡C—;

[0254] R is hydrogen or C₁-C₆ alkyl;

[0255] R² and R³ are independently

[0256] (a) hydrogen; or

[0257] (b) C₁-C₄ alkyl;

[0258] R⁴ is

[0259] (a) hydrogen;

[0260] (b) halogen;

[0261] (c) C₁-C₆ alkyl;

[0262] (d) C₁-C₄ alkoxy;

[0263] (e) C₁-C₄ acyloxy;

[0264] (f) C₁-C₄ alkylthio;

[0265] (g) C₁-C₄ alkylsulfinyl;

[0266] (h) C₁-C₄ alkylsulfonyl;

[0267] (i) hydroxy (C₁-C₄)alkyl;

[0268] (j) aryl (C₁-C₄)alkyl;

[0269] (k) —CO₂H;

[0270] (l) —CN;

[0271] (m) —CONHOR;

[0272] (n) —SO₂NHR;

[0273] (o)—NH₂;

[0274] (p) C₁-C₄ alkylamino;

[0275] (q) C₁-C₄ dialkylamino;

[0276] (r) —NHSO₂R;

[0277] (s) —NO₂;

[0278] (t) -aryl; or

[0279] (u) —OH;

[0280] R⁵ and R⁶ are independently C₁-C₈ alkyl or together form a C₃-C₁₀carbocyclic ring;

[0281] R⁷ and R⁸ are independently

[0282] (a) phenyl;

[0283] (b) a C₃-C₁₀ carbocyclic ring, saturated or unsaturated;

[0284] (c) a C₃-C₁₀ heterocyclic ring containing up to two heteroatoms,selected from —O—, —N— and —S—;

[0285] (d) H;

[0286] (e) C₁-C₆ alkyl; or

[0287] (f) form a 3 to 8 membered nitrogen containing ring with R⁵ orR⁶;

[0288] R⁷ and R⁸ in either linear or ring form may optionally besubstituted with up to three substituents independently selected fromC₁-C₆ alkyl, halogen, alkoxy, hydroxy and carboxy;

[0289] a ring formed by R⁷ and R⁸ may be optionally fused to a phenylring;

[0290] e is 0, 1 or 2;

[0291] m is 1, 2 or 3;

[0292] n is 0, 1 or 2;

[0293] p is 0, 1, 2 or 3;

[0294] q is 0, 1, 2 or 3;

[0295] and optical and geometric isomers thereof; and nontoxicpharmaceutically acceptable acid addition salts, N-oxides, esters,quaternary ammonium salts and prodrugs thereof.

[0296] Additional preferred compounds are disclosed in U.S. Pat. No.5,552,412 and are described by the formula designated herein as formula(IA):

[0297] wherein G is

[0298] R⁴ is H, OH, F, or Cl; and B and E are independently selectedfrom CH and N, and optical and geometric isomers thereof; and nontoxicpharmaceutically acceptable acid addition salts, N-oxides, esters,quaternary ammonium salts and prodrugs thereof.

[0299] Especially preferred compounds for the methods and kits of theinvention are:

[0300]cis-6-(4-fluoro-phenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol;

[0301](−)-cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol;

[0302]cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol;

[0303]cis-1-[6′-pyrrolidinoethoxy-3′-pyridyl]-2-phenyl-6-hydroxy-1,2,3,4-tetrahydronaphthalene;

[0304]1-(4′-pyrrolidinoethoxyphenyl)-2-(4″-fluorophenyl)-6-hydroxy-1,2,3,4-tetrahydroisoquinoline;

[0305]cis-6-(4-hydroxyphenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol;

[0306]1-(4′-pyrrolidinoethoxyphenyl)-2-phenyl-6-hydroxy-1,2,3,4-tetrahydroisoquinolineand pharmaceutically acceptable salts thereof.

[0307] An especially preferred salt of(−)-cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-olis the D-tartrate salt.

[0308] Other preferred estrogen agonists/antagonists are disclosed inU.S. Pat. No. 5,047,431. The structure of these compounds are describedby the formula designated herein as formula (II) below:

[0309] wherein

[0310] R^(1A) and R^(2A) may be the same or different and are either H,methyl, ethyl or a benzyl group; and optical or geometric isomersthereof; and pharmaceutically acceptable salts, N-oxides, esters,quaternary ammonium salts, and prodrugs thereof. A preferred compound isdroloxifene.

[0311] Additional preferred estrogen agonists/antagonists are thecompounds disclosed in U.S. Pat. No. 4,536,516; 4-hydroxy tamoxifen(i.e., tamoxifen wherein the 2-phenyl moiety has a hydroxy group at the4 position) and other compounds as disclosed in U.S. Pat. No. 4,623,660;raloxifene: (methanone,[6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]-,hydrochloride) and other compounds as disclosed in U.S. Pat. Nos.4,418,068; 5,393,763; 5,457,117; 5,478,847 and 5,641,790; toremifene:(ethanamine,2-[4-(4-chloro-1,2-diphenyl-1-butenyl)phenoxy]-N,N-dimethyl-, (Z)-,2-hydroxy-1,2,3-propanetricarboxylate (1:1) and other compounds asdisclosed in U.S. Pat. Nos. 4,696,949 and 4,996,225; centchroman:1-[2-[[4-(-methoxy-2,2,dimethyl-3-phenyl-chroman-4-yl)-phenoxy]-ethyl]-pyrrolidine and othercompounds as disclosed in U.S. Pat. No. 3,822,287; idoxifene:pyrrolidine, 1-[-[4-[[1-(4-iodophenyl)-2-phenyl-1-butenyl]phenoxy]ethyl]and other compounds as disclosed in U.S. Pat. No. 4,839,155;6-(4-hydroxy-phenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-naphthalen-2-oland other compounds as disclosed in U.S. Pat. No. 5,484,795; and{4-[2-(2-aza-bicyclo[2.2.1]hept-2-yl)-ethoxy]-phenyl}-[6-hydroxy-2-(4-hydroxy-phenyl)-benzo[b]thiophen-3-yl]-methanoneand other compounds as disclosed in published international patentapplication WO 95/10513. Other preferred compounds include GW 5638 andGW 7604, the synthesis of which is described in Willson et al., J. Med.Chem., 1994;37:1550-1552.

[0312] Further preferred estrogen agonists/antagonists include EM-652(as shown in the formula designated herein as formula (III) and EM-800(as shown in the formula designated herein as formula (IV)). Thesynthesis of EM-652 and EM-800 and the activity of various enantiomersis described in Gauthier et al., J. Med. Chem., 1997;40:2117-2122.

[0313] Further preferred estrogen agonists/antagonists include TSE 424and other compounds disclosed in U.S. Pat. No. 5,998,402, U.S. Pat. No.5,985,910, U.S. Pat. No. 5,780,497, U.S. Pat. No. 5,880,137, andEuropean Patent Application EP 0802183 A1 including the compoundsdescribed by the formulae designated herein as formulae V and VI, below:

[0314] wherein:

[0315] R_(1B) is selected from H, OH or the C₁-C₁₂ esters (straightchain or branched) or C₁-C₁₂ (straight chain or branched or cyclic)alkyl ethers thereof, or halogens; or C₁-C₄ halogenated ethers includingtrifluoromethyl ether and trichloromethyl ether.

[0316] R_(2B), R_(3B), R_(4B), R_(5B), and R_(6B) are independentlyselected from H, OH or the C₁-C₁₂ esters (straight chain or branched) orC—CO₁₂ alkyl ethers (straight chain or branched or cyclic) thereof,halogens, or C₁-C₄ halogenated ethers including trifluoromethyl etherand trichloromethyl ether, cyano, C₁-C₆ alkyl (straight chain orbranched), or trifluoromethyl;

[0317] X_(A) is selected from H, C₁-C₆ alkyl, cyano, nitro,trifluoromethyl, and halogen;

[0318] s is 2 or 3;

[0319] Y_(A) is selected from:

[0320] a) the moiety:

[0321] wherein R_(7B) and R_(8B) are independently selected from thegroup of H, C₁-C₆ alkyl, or phenyl optionally substituted by CN, C₁-C₆alkyl (straight chain or branched), C₁-C₆ alkoxy (straight chain orbranched), halogen, —OH, —CF₃, or —OCF₃;

[0322] b) a five-membered saturated, unsaturated or partiallyunsaturated heterocycle containing up to two heteroatoms selected fromthe group consisting of —O—, —NH—, —N(C₁-C₄ alkyl)-, —N═, and—S(O)_(u)—, wherein u is an integer of from 0-2, optionally substitutedwith 1-3 substituents independently selected from the group consistingof hydrogen, hydroxyl, halo, C₁-C₄ alkyl, trihalomethyl, C₁-C₄ alkoxy,trihalomethoxy, C₁-C₄ acyloxy, C₁-C₄ alkylthio, C₁-C₄ alkylsulfinyl,C₁-C₄ alkylsulfonyl, hydroxy (C₁-C₄)alkyl, —CO₂H, —CN, —CONHR_(1B),—NH₂, C₁-C₄ alkylamino, di(C₁-C₄)alkylamino, —NHSO₂R_(1B), —NHCOR_(1B),—NO₂, and phenyl optionally substituted with 1-3 (C₁-C₄)alkyl;

[0323] c) a six-membered saturated, unsaturated or partially unsaturatedheterocycle containing up to two heteroatoms selected from the groupconsisting of —O—, —NH—, —N(C₁-C₄ alkyl)-, —N═, and —S(O)_(u)—, whereinu is an integer of from 0-2, optionally substituted with 1-3substituents independently selected from the group consisting ofhydrogen, hydroxyl, halo, C₁-C₄ alkyl, trihalomethyl, C₁-C₄ alkoxy,trihalomethoxy, C₁-C₄ acyloxy, C₁-C₄ alkylthio, C₁-C₄ alkylsulfinyl,C₁-C₄ alkylsulfonyl, hydroxy (C₁-C₄)alkyl, —CO₂H, —CN, —CONHR₁, —NH₂,C₁-C₄ alkylamino, di(C₁-C₄)alkylamino, —NHSO₂R_(1B), —NHCOR_(1B), —NO₂,and phenyl optionally substituted with 1-3 (C₁-C₄)alkyl;

[0324] d) a seven-membered saturated, unsaturated or partiallyunsaturated heterocycle containing up to two heteroatoms selected fromthe group consisting of —O—, —NH—, —N(C₁-C₄ alkyl)-, —N═, and—S(O)_(u)—, wherein u is an integer of from 0-2, optionally substitutedwith 1-3 substituents independently selected from the group consistingof hydrogen, hydroxyl, halo, C₁-C₄ alkyl, trihalomethyl, C₁-C₄ alkoxy,trihalomethoxy, C₁-C₄ acyloxy, C₁-C₄ alkylthio, C₁-C₄ alkylsulfinyl,C₁-C₄ alkylsulfonyl, hydroxy (C₁-C₄)alkyl, —CO₂H, —CN, —CONHR_(1B),—NH₂, C₁-C₄ alkylamino, di(C₁-C₄)alkylamino, —NHSO₂R_(1B), —NHCOR_(1B),—NO₂, and phenyl optionally substituted with 1-3 (C₁-C₄)alkyl; or

[0325] e) a bicyclic heterocycle containing from 6-12 carbon atomseither bridged or fused and containing up to two heteroatoms selectedfrom the group consisting of —O—, —NH—, —N(C₁-C₄ alkyl)-, and—S(O)_(u)—, wherein u is an integer of from 0-2, optionally substitutedwith 1-3 substituents independently selected from the group consistingof hydrogen, hydroxyl, halo, C₁-C₄ alkyl, trihalomethyl, C₁-C₄ alkoxy,trihalomethoxy, C₁-C₄ acyloxy, C₁-C₄ alkylthio, C₁-C₄ alkylsulfinyl,C₁-C₄ alkylsulfonyl, hydroxy (C₁-C₄)alkyl, —CO₂H—, —CN—, —CONHR_(1B)—,—NH₂, —N═, C₁-C₄ alkylamino, di(C₁-C₄)alkylamino, —NHSO₂R_(1B),—NHCOR_(1B), —NO₂, and phenyl optionally substituted with 1-3 (C₁-C₄)alkyl; and optical and geometric isomers thereof; and nontoxicpharmaceutically acceptable acid addition salts, N-oxides, esters,quaternary ammonium salts, and prodrugs thereof.

[0326] Preferred compounds of this invention are those having thegeneral structures V or VI, above, wherein:

[0327] R_(1B) is selected from H, OH or the C₁-C₁₂ esters or alkylethers thereof, and halogen;

[0328] R_(2B), R_(3B), R_(4B), R_(5B), and R_(6B) are independentlyselected from H, OH or the C₁-C₁₂ esters or alkyl ethers thereof,halogen, cyano, C₁-C₆ alkyl, or trihalomethyl, preferablytrifluoromethyl, with the proviso that, when R_(1B) is H, R_(2B) is notOH;

[0329] X_(A) is selected from H, C₁-C₆ alkyl, cyano, nitro,trifluoromethyl, and halogen;

[0330] Y_(A) is the moiety:

[0331] R_(7B) and R_(8B) are selected independently from H, C₁-C₆ alkyl,or combined by —(CH₂)_(w)—, wherein w is an integer of from 2 to 6, soas to form a ring, the ring being optionally substituted by up to threesubstituents selected from the group of hydrogen, hydroxyl, halo, C₁-C₄alkyl, trihalomethyl, C₁-C₄ alkoxy, trihalomethoxy, C₁-C₄ alkylthio,C₁-C₄ alkylsulfinyl, C₁-C₄ alkylsulfonyl, hydroxy (C₁-C₄)alkyl, —CO₂H,—CN, —CONH(C₁-C₄alkyl), —NH₂, C₁-C₄ alkylamino, C₁-C₄ dialkylamino,—NHSO₂(C₁-C₄alkyl), —CO(C₁-C₄alkyl), and —NO₂; and optical and geometricisomers thereof; and nontoxic pharmaceutically acceptable acid additionsalts, N-oxides, esters, quaternary ammonium salts, and prodrugsthereof.

[0332] The rings formed by a concatenated R_(7B) and R_(8B), mentionedabove, may include, but are not limited to, aziridine, azetidine,pyrrolidine, piperidine, hexamethyleneamine or heptamethyleneaminerings.

[0333] Preferred compounds of structural formulas V and VI, above, arethose wherein R_(1B) is OH; R_(2B)-R_(6B) are as defined above; X_(A) isselected from the group of Cl, NO₂, CN, CF₃, or CH₃; Y_(A) is the moiety

[0334] and R_(7B) and R_(8B) are concatenated together as —(CH₂)_(t)—,wherein t is an integer of from 4 to 6, to form a ring optionallysubstituted by up to three subsituents selected from the group ofhydrogen, hydroxyl, halo, C₁-C₄ alkyl, trihalomethyl, C₁-C₄ alkoxy,trihalomethoxy, C₁-C₄ alkylthio, C₁-C₄ alkylsulfinyl, C₁-C₄alkylsulfonyl, hydroxy (C₁-C₄)alkyl, —CO₂H, —CN, —CONH(C₁-C₄)alkyl,—NH₂, C₁-C₄ alkylamino, di(C₁-C₄)alkylamino, —NHSO₂(C₁-C₄)alkyl,—NHCO(C₁-C₄)alkyl, and —NO₂; and optical and geometric isomers thereof;and nontoxic pharmaceutically acceptable acid addition salts, N-oxides,esters, quaternary ammonium salts, and prodrugs thereof.

[0335] Another preferred compound is TSE-424 as described by the formuladesignated herein as formula (Va) below:

[0336] The estrogen agonists/antagonists of this invention can beadministered in the form of pharmaceutically acceptable salts. The saltsare conveniently formed, as is usual in organic chemistry, by reactingthe compound, when basic, with a suitable acid. The salts usually arequickly formed in high yields at moderate temperatures, and often areprepared by merely isolating the compound from a suitable acidic wash asthe final step of the synthesis. The salt-forming acid is dissolved inan appropriate organic solvent, or aqueous organic solvent, such as analkanol, ketone or ester. On the other hand, if the compound is desiredin the free base form, it is isolated from a basic final wash step,according to the usual practice. A preferred technique for preparinghydrochlorides is to dissolve the free base in a suitable solvent anddry the solution thoroughly, as over molecular sieves, before bubblinghydrogen chloride gas through it. A preferred salt of(−)-cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-olis the D-(−)-tartrate salt. It will also be recognized that it ispossible to administer amorphous forms of the estrogenagonists/antagonists.

[0337] The expression “pharmaceutically acceptable salts” includes bothpharmaceutically acceptable acid addition salts and pharmaceuticallyacceptable cationic salts. The expression “pharmaceutically acceptablecationic salts” is intended to define, but is not limited to, such saltsas the alkali metal salts, (e.g., sodium and potassium), alkaline earthmetal salts (e.g., calcium and magnesium), aluminum salts, ammoniumsalts, and salts with organic amines such as benzathine(N,N′-dibenzylethylenediamine), choline, diethanolamine,ethylenediamine, meglumine (N-methylglucamine), benethamine(N-benzylphenethylamine), diethylamine, piperazine, tromethamine(2-amino-2-hydroxymethyl-1,3-propanediol) and procaine. The expression“pharmaceutically acceptable acid addition salts” is intended to define,but is not limited to, such salts as the hydrochloride, hydrobromide,sulfate, hydrogen sulfate, phosphate, hydrogen phosphate,dihydrogenphosphate, acetate, succinate, citrate, methanesulfonate(mesylate) and p-toluenesulfonate (tosylate) salts.

[0338] One of ordinary skill in the art will recognize that certainestrogen agonists/antagonists of this invention will contain one or moreatoms which may be in a particular stereochemical, tautomeric, orgeometric configuration, giving rise to stereoisomers, tautomers andconfigurational isomers. All such tautomers and isomers and mixturesthereof are included in this invention. Hydrates and solvates of thecompounds of this invention are also included.

[0339] The subject invention also includes isotopically-labeled estrogenagonists/antagonists, which are structurally identical to thosedisclosed above, but for the fact that one or more atoms are replaced byan atom having an atomic mass or mass number different from the atomicmass or mass number usually found in nature. Examples of isotopes thatcan be incorporated into compounds of the invention include isotopes ofhydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine andchlorine, such as ²H, ³H, ¹³C, ¹⁴C, ¹⁵N ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F and³⁶Cl, respectively. Compounds of the present invention, prodrugsthereof, and pharmaceutically acceptable salts of said compounds and ofsaid prodrugs which contain the aforementioned isotopes and/or otherisotopes of other atoms are within the scope of this invention. Certainisotopically labeled compounds of the present invention, for examplethose into which radioactive isotopes such as ³H and ¹⁴C areincorporated, are useful in drug and/or substrate tissue distributionassays. Tritiated, i.e., ³H, and carbon-14, i.e., ¹⁴C, isotopes areparticularly preferred for their ease of preparation and detectability.Further, substitution with heavier isotopes such as deuterium, i.e., ²H,may afford certain therapeutic advantages resulting from greatermetabolic stability, for example increased in vivo half-life or reduceddosage requirements and, hence, may be preferred in some circumstances.Isotopically labeled compounds of this invention and prodrugs thereofcan generally be prepared by carrying out known or referenced proceduresand by substituting a readily available isotopically labeled reagent fora non-isotopically labeled reagent.

[0340] Those of ordinary skill in the art will recognize thatphysiologically active compounds which have accessible hydroxy groupscan be administered in the form of pharmaceutically acceptable esters.The compounds of this invention can be effectively administered as anester, formed on the hydroxy groups. It is possible, as has long beenknown in pharmaceutical chemistry, to adjust the rate or duration ofaction of the compound by appropriate choices of ester groups.

[0341] Certain ester groups are preferred when a compound of thisinvention contains an ester. The estrogen agonists/antagonists includingthe compounds of formula I, IA, II, III, IV, V, Va, or VI may containester groups at various positions as defined herein above, where thesegroups are represented as —COOR, R is C₁-C₁₄ alkyl, C₁-C₃ chloroalkyl,C₁-C₃ fluoroalkyl, C₅-C₇ cycloalkyl, phenyl, or phenyl mono- ordisubstituted with C₁-C₄ alkyl, C₁-C₄ alkoxy, hydroxy, nitro, chloro,fluoro or tri(chloro or fluoro)methyl.

[0342] The dose of a compound of this invention to be administered to asubject is rather widely variable and subject to the judgement of theattending physician. It should be noted that it may be necessary toadjust the dose of a compound when it is administered in the form of asalt, such as a laureate, the salt forming moiety of which has anappreciable molecular weight. The particular dose of a compoundadministered according to this invention will be determined by thecircumstances including, for example, the compound administered, theroute of administration, and the severity of the condition beingtreated.

[0343] The following dosage amounts are for an average human subjecthaving a weight of about 65 kg to about 70 kg. The skilled practitionerwill readily be able to determine the dosage amount required for asubject whose weight falls outside the 65 kg to 70 kg range, based uponthe medical history of the subject. All doses set forth herein are dailydoses of the free base form of the estrogen agonists/antagonists.Calculation of the dosage amount for other forms of the free base formsuch as salts or hydrates is easily accomplished by performing a simpleratio relative to the molecular weights of the species involved.

[0344] The general range of effective administration rates of anestrogen agonist/antagonist is from about 0.001 mg/day to about 200mg/day. A preferred rate range is from about 0.010 mg/day to about 100mg/day. Of course, it is often practical to administer the daily dose ofcompound in portions, at various hours of the day. However, in any givencase, the amount of compound administered will depend on such factors asthe potency of the specific estrogen agonist/antagonist, the solubilityof the compound, the formulation used and the route of administration.

[0345] Methods of formulation are well known in the art and aredisclosed, for example, in Remington: The Science and Practice ofPharmacy, Mack Publishing Company, Easton, Pa., 19th Edition (1995).Pharmaceutical compositions for use within the present invention can bein the form of sterile, non-pyrogenic liquid solutions or suspensions,coated capsules, suppositories, lyophilized powders, transdermal patchesor other forms known in the art.

[0346] Capsules are prepared by mixing the compound with a suitablediluent and filling the proper amount of the mixture in capsules. Theusual diluents include inert powdered substances such as starch of manydifferent kinds, powdered cellulose, especially crystalline andmicrocrystalline cellulose, sugars such as fructose, mannitol andsucrose, grain flours and similar edible powders.

[0347] Tablets are prepared by direct compression, by wet granulation,or by dry granulation. Their formulations usually incorporate diluents,binders, lubricants and disintegrators as well as the compound. Typicaldiluents include, for example, various types of starch, lactose,mannitol, kaolin, calcium phosphate or sulfate, inorganic salts such assodium chloride and powdered sugar. Powdered cellulose derivatives arealso useful. Typical tablet binders are substances such as starch,gelatin and sugars such as lactose, fructose, glucose and the like.Natural and synthetic gums are also convenient, including acacia,alginates, methylcellulose, polyvinylpyrrolidine and the like.Polyethylene glycol, ethylcellulose and waxes can also serve as binders.

[0348] A lubricant may be necessary in a tablet formulation to preventthe tablet and punches from sticking in the die. The lubricant is chosenfrom such slippery solids as talc, magnesium and calcium stearate,stearic acid and hydrogenated vegetable oils.

[0349] Tablet disintegrators are substances that facilitate thedisintegration of a tablet to release a compound when the tablet becomeswet. They include starches, clays, celluloses, algins and gums, moreparticularly, corn and potato starches, methylcellulose, agar,bentonite, wood cellulose, powdered natural sponge, cation-exchangeresins, alginic acid, guar gum, citrus pulp and carboxymethylcellulose,for example, may be used as well as sodium lauryl sulfate.

[0350] Tablets are often coated with sugar as a flavorant and sealant,or with film-forming protecting agents to modify the dissolutionproperties of the tablet. The compounds may also be formulated aschewable tablets, by using large amounts of pleasant-tasting substancessuch as mannitol in the formulation, as is now well-established in theart.

[0351] When it is desired to administer a compound as a suppository, thetypical bases may be used. Cocoa butter is a traditional suppositorybase, which may be modified by addition of waxes to raise its meltingpoint slightly. Water-miscible suppository bases comprising,particularly, polyethylene glycols of various molecular weights are inwide use.

[0352] The effect of the compounds may be delayed or prolonged by properformulation. For example, a slowly soluble pellet of the compound may beprepared and incorporated in a tablet or capsule. The technique may beimproved by making pellets of several different dissolution rates andfilling capsules with a mixture of the pellets. Tablets or capsules maybe coated with a film that resists dissolution for a predictable periodof time. Topical formulations may be designed to yield delayed and/orprolonged percutaneous absorption of a compound. Even the parenteralpreparations may be made long-acting, by dissolving or suspending thecompound in oily or emulsified vehicles which allow it to disperse onlyslowly in the serum.

[0353] The term “prodrug” means a compound that is transformed in vivoto yield a compound of the present invention. The transformation mayoccur by various mechanisms, such as through hydrolysis in blood. Adiscussion of the use of prodrugs is provided by T. Higuchi and W.Stella, “Pro-drugs as Novel Delivery Systems,” Vol. 14 of the A.C.S.Symposium Series, and in Bioreversible Carriers in Drug Design, ed.Edward B. Roche, American Pharmaceutical Association and Pergamon Press,1987.

[0354] For example, if a compound of the present invention contains acarboxylic acid functional group, a prodrug can comprise an ester formedby the replacement of the hydrogen atom of the acid group with a groupsuch as (C₁-C₈)alkyl, (C₂-C₁₂)alkanoyloxymethyl, 1-(alkanoyloxy)ethylhaving from 4 to 9 carbon atoms, 1-methyl-1-(alkanoyloxy)-ethyl havingfrom 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6carbon atoms, 1-(alkoxycarbonyloxy)ethyl having from 4 to 7 carbonatoms, 1-methyl-1-(alkoxycarbonyloxy)ethyl having from 5 to 8 carbonatoms, N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms,1-(N-(alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon atoms,3-phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-4-yl,di-N,N-(C₁-C₂)alkylamino(C₂-C₃)alkyl (such as β-dimethylaminoethyl),carbamoyl-(C₁-C₂)alkyl, N,N-di(C₁-C₂)alkylcarbamoyl-(C₁-C₂)alkyl andpiperidino-, pyrrolidino- or morpholino(C₂-C₃)alkyl.

[0355] Similarly, if a compound of the present invention comprises analcohol functional group, a prodrug can be formed by the replacement ofthe hydrogen atom of the alcohol group with a group such as(C₁-C₆)alkanoyloxymethyl, 1-((C₁-C₆)alkanoyloxy)ethyl,1-methyl-1-((C₁-C₆)alkanoyloxy) ethyl, (C₁-C₆)alkoxycarbonyloxymethyl,N-(C₁-C₆)alkoxycarbonylaminomethyl, succinoyl, (C₁-C₆)alkanoyl,α-amino(C₁-C₄) alkanoyl, arylacyl and α-aminoacyl, orα-aminoacyl-α-aminoacyl, where each α-aminoacyl group is independentlyselected from the naturally occurring L-amino acids, P(O)(OH)₂,—P(O)(O(C₁-C₆)alkyl)₂ or glycosyl (the radical resulting from theremoval of a hydroxyl group of the hemiacetal form of a carbohydrate).

[0356] If a compound of the present invention comprises an aminefunctional group, a prodrug can be formed by the replacement of ahydrogen atom in the amine group with a group such as R^(X)-carbonyl,R^(X)O-carbonyl, NR^(X)R^(X)′-carbonyl where R^(X) and R^(X)′ are eachindependently (C₁-C₁₀)alkyl, (C₃-C₇)cycloalkyl, benzyl, orR_(X)-carbonyl is a natural α-aminoacyl or natural α-aminoacyl-naturalα-aminoacyl, —C(OH)C(O)OY^(X) wherein Y^(X) is H, (C₁-C₆)alkyl orbenzyl), —C(OY^(X0)) Y^(X1) wherein Y^(X0) is (C₁-C₄) alkyl and Y^(X1)is (C₁-C₆)alkyl, carboxy(C₁-C₆)alkyl, amino(C₁-C₄)alkyl or mono-N- ordi-N,N-(C₁-C₆)alkylaminoalkyl, —C(Y^(X2)) Y^(X3) wherein Y^(X2) is H ormethyl and Y^(X3) is mono-N- or di-N,N-(C₁-C₆)alkylamino, morpholino,piperidin-1-yl or pyrrolidin-1-yl.

[0357] Advantageously, the present invention also provides kits for useby a consumer to treat cancer of the liver, ovarian cancer, a desmoidtumor, glioma, pancreatic cancer, or renal cell carcinoma. The kitscomprise a) a pharmaceutical composition comprising an estrogenagonist/antagonist; and b) instructions describing methods of using thepharmaceutical compositions to treat cancer of the liver, ovariancancer, a desmoid tumor, glioma, pancreatic cancer, or renal cellcarcinoma.

[0358] A “kit” as used in the instant application includes a containerfor containing the pharmaceutical compositions and may also includedivided containers such as a divided bottle or a divided foil packet.The container can be in any conventional shape or form as known in theart which is made of a pharmaceutically acceptable material, for examplea paper or cardboard box, a glass or plastic bottle or jar, a resealablebag (for example, to hold a “refill” of tablets for placement into adifferent container), or a blister pack with individual doses forpressing out of the pack according to a therapeutic schedule. Thecontainer employed can depend on the exact dosage form involved, forexample a conventional cardboard box would not generally be used to holda liquid suspension. It is feasible that more than one container can beused together in a single package to market a single dosage form. Forexample, tablets may be contained in a bottle, which is in turncontained within a box.

[0359] An example of such a kit is a so-called blister pack. Blisterpacks are well known in the packaging industry and are being widely usedfor the packaging of pharmaceutical unit dosage forms (tablets,capsules, and the like). Blister packs generally consist of a sheet ofrelatively stiff material covered with a foil of a preferablytransparent plastic material. During the packaging process, recesses areformed in the plastic foil. The recesses have the size and shape ofindividual tablets or capsules to be packed or may have the size andshape to accommodate multiple tablets and/or capsules to be packed.Next, the tablets or capsules are placed in the recesses accordingly andthe sheet of relatively stiff material is sealed against the plasticfoil at the face of the foil which is opposite from the direction inwhich the recesses were formed. As a result, the tablets or capsules areindividually sealed or collectively sealed, as desired, in the recessesbetween the plastic foil and the sheet. Preferably, the strength of thesheet is such that the tablets or capsules can be removed from theblister pack by manually applying pressure on the recesses whereby anopening is formed in the sheet at the place of the recess. The tablet orcapsule can then be removed via said opening.

[0360] It may be desirable to provide a written memory aid, where thewritten memory aid is of the type containing information and/orinstructions for the physician, pharmacist or other health careprovider, or patient, e.g., in the form of numbers next to the tabletsor capsules whereby the numbers correspond with the days of the regimenwhich the tablets or capsules so specified should be ingested or a cardwhich contains the same type of information. Another example of such amemory aid is a calendar printed on the card e.g., as follows “FirstWeek, Monday, Tuesday,” . . . etc. . . . “Second Week, Monday, Tuesday,. . . ” etc. Other variations of memory aids will be readily apparent. A“daily dose” can be a single tablet or capsule or several tablets orcapsules to be taken on a given day.

[0361] Another specific embodiment of a kit is a dispenser designed todispense the daily doses one at a time. Preferably, the dispenser isequipped with a memory-aid, so as to further facilitate compliance withthe regimen. An example of such a memory-aid is a mechanical counterwhich indicates the number of daily doses that has been dispensed.Another example of such a memory-aid is a battery-powered micro-chipmemory coupled with a liquid crystal readout, or audible reminder signalwhich, for example, reads out the date that the last daily dose has beentaken and/or reminds one when the next dose is to be taken.

[0362] The kits of the present invention may also include, in additionto an estrogen agonist/antagonist, one or more additionalpharmaceutically active compounds. Preferably, the additional compoundis another estrogen agonist/antagonist or another compound useful totreat cancer of the liver, ovarian cancer, a desmoid tumor, glioma,pancreatic cancer, or renal cell carcinoma. The additional compound orcompounds may be administered in the same dosage form as the estrogenagonist/antagonist or in different dosage forms. Likewise, theadditional compounds can be administered at the same time as theestrogen agonist/antagonist or at different times.

[0363] Compounds that are used to treat cancer of the liver, ovariancancer, a desmoid tumor, glioma, pancreatic cancer, or renal cellcarcinoma and which can be used in combination with the estrogenagonists/antagonists of the present invention include 5-fluorouracil;cisplatin; paclitaxel; onconase; topotecan; hexamethylamine; ifsofamide;doxorubicin; etoposide; bleomycin; nitrosoureas such as carmustine,lomustine, procarbazine, semustine, and vincristine; methotrexate;carboplatin; actinomycin D; and streptozocin. The estrogenagonists/antagonists of the present invention can also be used incombination with radiation therapy.

[0364] All documents cited herein, including patents and patentapplications, are hereby incorporated by reference.

What is claimed is:
 1. A method of treating cancer of the liver, ovariancancer, a desmoid tumor, glioma, pancreatic cancer, or renal cellcarcinoma, the method comprising the step of administering to a patienthaving cancer of the liver, ovarian cancer, a desmoid tumor, glioma,pancreatic cancer, or renal cell carcinoma a therapeutically effectiveamount of an estrogen agonist/antagonist that is a compound of formula(I):

wherein: A is selected from CH₂ and NR; B, D and E are independentlyselected from CH and N; Y is (a) phenyl, optionally substituted with 1-3substituents independently selected from R⁴; (b) naphthyl, optionallysubstituted with 1-3 substituents independently selected from R⁴; (c)C₃-C₈ cycloalkyl, optionally substituted with 1-2 substituentsindependently selected from R⁴; (d) C₃-C₈ cycloalkenyl, optionallysubstituted with 1-2 substituents independently selected from R⁴; (e) afive membered heterocycle containing up to two heteroatoms selected fromthe group consisting of —O—, —NR²— and —S(O)_(n)—, optionallysubstituted with 1-3 substituents independently selected from R⁴; (f) asix membered heterocycle containing up to two heteroatoms selected fromthe group consisting of —O—, —NR²— and —S(O)_(n)— optionally substitutedwith 1-3 substituents independently selected from R⁴; or (g) a bicyclicring system consisting of a five or six membered heterocyclic ring fusedto a phenyl ring, said heterocyclic ring containing up to twoheteroatoms selected from the group consisting of —O—, —NR²— and—S(O)_(n)—, optionally substituted with 1-3 substituents independentlyselected from R⁴; Z¹ is (a) —(CH₂)_(p) W(CH₂)_(q)—; (b) —O(CH₂)_(p)CR⁵R⁶—; (c) —O(CH₂)_(p)W(CH₂)_(q)—; (d) —OCHR²CHR³—; or (e) —SCHR²CHR³;G is (a) —NR⁷R⁸;

wherein n is 0, 1 or 2; m is 1, 2 or 3; Z² is —NH—, —O—, —S—, or —CH₂—;optionally fused on adjacent carbon atoms with one or two phenyl ringsand, optionally independently substituted on carbon with one to threesubstituents and, optionally, independently on nitrogen with achemically suitable substituent selected from R⁴; or (c) a bicyclicamine containing five to twelve carbon atoms, either bridged or fusedand optionally substituted with 1-3 substituents independently selectedfrom R⁴; or Z¹ and G in combination may be

W is (a) —CH₂—; (b) —CH═CH—; (c) —O—; (d) —NR²—; (e) —S(O)_(n)—;

(g) —CR²(OH)—; (h) —CONR²—; (i) —NR²CO—;

(k) —C≡C—; R is hydrogen or C₁-C₆ alkyl; R² and R³ are independently (a)hydrogen; or (b) C₁-C₄ alkyl; R⁴ is (a) hydrogen; (b) halogen; (c) C₁-C₆alkyl; (d) C₁-C₄ alkoxy; (e) C₁-C₄ acyloxy; (f) C₁-C₄ alkylthio; (g)C₁-C₄ alkylsulfinyl; (h) C₁-C₄ alkylsulfonyl; (i) hydroxy (C₁-C₄)alkyl;(j) aryl (C₁-C₄)alkyl; (k) —CO₂H; (l) —CN; (m) —CONHOR; (n) —SO₂NHR;(o)—NH₂; (p) C₁-C₄ alkylamino; (q) C₁-C₄ dialkylamino; (r) —NHSO₂R; (s)—NO₂; (t) -aryl; or (u) —OH; R⁵ and R⁶ are independently C₁-C₈ alkyl ortogether form a C₃-C₁₀ carbocyclic ring; R⁷ and R⁸ are independently (a)phenyl; (b) a C₃-C₁₀ carbocyclic ring, saturated or unsaturated; (c) aC₃-C₁₀ heterocyclic ring containing up to two heteroatoms, selected from—O—, —N— and —S—; (d) H; (e) C₁-C₆ alkyl; or (f) form a 3 to 8 memberednitrogen containing ring with R⁵ or R⁶; R⁷ and R⁸ in either linear orring form may optionally be substituted with up to three substituentsindependently selected from C₁-C₆ alkyl, halogen, alkoxy, hydroxy andcarboxy; a ring formed by R⁷ and R⁸ may be optionally fused to a phenylring; e is 0, 1 or 2; m is 1, 2 or 3; n is 0, 1 or 2; p is 0, 1, 2 or 3;q is 0, 1, 2 or 3; or an optical or geometric isomer thereof; or apharmaceutically acceptable salt, N-oxide, ester, quaternary ammoniumsalt or prodrug thereof.
 2. The method of claim 1 wherein the estrogenagonist/antagonist is a compound of formula (IA)

wherein G is

R⁴ is H, OH, F, or Cl; and B and E are independently selected from CHand N or an optical or geometric isomer thereof; or a pharmaceuticallyacceptable salt, N-oxide, ester, quaternary ammonium salt, or a prodrugthereof.
 3. The method of claim 1 wherein the estrogenagonist/antagonist is(−)-cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-olor an optical or geometric isomer thereof; a pharmaceutically acceptablesalt, N-oxide, ester, quaternary ammonium salt, or a prod rug thereof.4. The method of claim 1 wherein the estrogen agonist/antagonist is(−)-cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol,D-tartrate salt.
 5. A method of treating cancer of the liver, ovariancancer, a desmoid tumor, glioma, pancreatic cancer, or renal cellcarcinoma, the method comprising the step of administering to a patienthaving cancer of the liver, ovarian cancer, a desmoid tumor, glioma,pancreatic cancer, or renal cell carcinoma a therapeutically effectiveamount of an estrogen agonist/antagonist compound selected from: A)4-hydroxy tamoxifen, droloxifene, toremifene, centchroman, idoxifene,raloxifene,6-(4-hydroxy-phenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-naphthalen-2-ol,{4-[2-(2-aza-bicyclo[2.2.1]hept-2-yl)-ethoxy]-phenyl}-[6-hydroxy-2-(4-hydroxy-phenyl)-benzo[b]thiophen-3-yl]-methanone,EM-652, EM-800, GW 5638, GW 7604, or an optical or geometric isomerthereof; pharmaceutically acceptable salt, N-oxide, ester, quaternaryammonium salt, or prodrug thereof; B) a compound of formula V or VI:

wherein: R_(1B) is selected from H, OH, —O—C(O)—C₁-C₁₂ alkyl (straightchain or branched), —O—C₁-C₁₂ alkyl (straight chain or branched orcyclic), or halogens or C₁-C₄ halogenated ethers; R_(2B), R_(3B),R_(4B), R_(5B), and R_(6B) are independently selected from H, OH,—O—C(O)—C₁-C₁₂ (straight chain or branched), —O—C₁-C₁₂ (straight chainor branched or cyclic), halogens, or C₁-C₄ halogenated ethers, cyano,C₁-C₆ alkyl (straight chain or branched), or trifluoromethyl; X_(A) isselected from H, C₁-C₆ alkyl, cyano, nitro, trifluoromethyl, andhalogen; s is 2 or 3; Y_(A) is the moiety:

wherein: a) R_(7B) and R_(8B) are independently selected from the groupof H, C₁-C₆ alkyl, or phenyl optionally substituted by CN, C₁-C₆ alkyl(straight chain or branched), C₁-C₆ alkoxy (straight chain or branched),halogen, —OH, —CF₃, or —OCF₃; or b) R_(7B) and R_(8B) are concatenatedto form a five-membered saturated heterocycle containing one nitrogenheteroatom, the heterocycle being optionally substituted with 1-3substituents independently selected from the group consisting ofhydrogen, hydroxyl, halo, C₁-C₄ alkyl, trihalomethyl, C₁-C₄ alkoxy,trihalomethoxy, C₁-C₄ acyloxy, C₁-C₄ alkylthio, C₁-C₄ alkylsulfinyl,C₁-C₄ alkylsulfonyl, hydroxy (C₁-C₄)alkyl, —CO₂H, —CN, —CONHR_(1B),—NH₂, —NH(C₁-C₄ alkyl), —N(C₁-C₄ alkyl)₂, —NHSO₂R_(1B), —NHCOR_(1B),—NO₂, or phenyl optionally substituted with 1-3 (C₁-C₄)alkyl; or c)R_(7B) and R_(8B) are concatenated to form a six-membered saturatedheterocycle containing one nitrogen heteroatom, the heterocycle beingoptionally substituted with 1-3 substituents independently selected fromthe group consisting of hydrogen, hydroxyl, halo, C₁-C₄ alkyl,trihalomethyl, C₁-C₄ alkoxy, trihalomethoxy, C₁-C₄ acyloxy, C₁-C₄alkylthio, C₁-C₄alkylsulfinyl, C₁-C₄ alkylsulfonyl, hydroxy(C₁-C₄)alkyl, —CO₂H, —CN, —CONHR_(1B), —NH₂, —NH(C₁-C₄ alkyl), —N(C₁-C₄alkyl)₂, —NHSO₂R_(1B), —NHCOR_(1B), —NO₂, or phenyl optionallysubstituted with 1-3 (C₁-C₄)alkyl; or d) R_(7B) and R_(8B) areconcatenated to form a seven-membered saturated heterocycle containingone nitrogen heteroatom, the heterocycle being optionally substitutedwith 1-3 substituents independently selected from the group consistingof hydrogen, hydroxyl, halo, C₁-C₄ alkyl, trihalomethyl, C₁-C₄ alkoxy,trihalomethoxy, C₁-C₄ acyloxy, C₁-C₄ alkylthio, C₁-C₄ alkylsulfinyl,C₁-C₄ alkylsulfonyl, hydroxy (C₁-C₄)alkyl, —CO₂H, —CN, —CONHR_(1B),—NH₂, —NH(C₁-C₄ alkyl), —N(C₁-C₄ alkyl)₂, —NHSO₂ R_(1B), —NHCOR_(1B),—NO₂, or phenyl optionally substituted with 1-3 (C₁-C₄)alkyl; or e)R_(7B) and R_(8B) are concatenated to form an eight-membered saturatedheterocycle containing one nitrogen heteroatom, the heterocycle beingoptionally substituted with 1-3 substituents independently selected fromthe group consisting of hydrogen, hydroxyl, halo, C₁-C₄ alkyl,trihalomethyl, C₁-C₄ alkoxy, trihalomethoxy, C₁-C₄ acyloxy, C₁-C₄alkylthio, C₁-C₄ alkylsulfinyl, C₁-C₄ alkylsulfonyl, hydroxy(C₁-C₄)alkyl, —CO₂H, —CN, —CONHR_(1B), —NH₂, —NH(C₁-C₄ alkyl),—N(C₁-C₄alkyl)₂, —NHSO₂R_(1B), —NHCOR_(1B), —NO₂, or phenyl optionallysubstituted with 1-3 (C₁-C₄)alkyl; or f) R_(7B) and R_(8B) areconcatenated to form a saturated bicyclic heterocycle containing from6-12 carbon atoms either bridged or fused and containing one nitrogenheteroatom, the heterocycle being optionally substituted with 1-3substituents independently selected from the group consisting ofhydrogen, hydroxyl, halo, C₁-C₄ alkyl, trihalomethyl, C₁-C₄ alkoxy,trihalomethoxy, C₁-C₄ acyloxy, C₁-C₄ alkylthio, C₁-C₄ alkylsulfinyl,C₁-C₄ alkylsulfonyl, hydroxy (C₁-C₄)alkyl, —CO₂H, —CN, —CONHR_(1B),—NH₂, —NH(C₁-C₄ alkyl), —N(C₁-C₄ alkyl)₂, —NHSO₂R_(1B), —NHCOR_(1B),—NO₂, or phenyl optionally substituted with 1-3 (C₁-C₄) alkyl; or anoptical or geometric isomer thereof; or a pharmaceutically acceptablesalt, N-oxide, ester, quaternary ammonium salt or prodrug thereof; C)the compound of formula Va:

or an optical or geometric isomer thereof; or a pharmaceuticallyacceptable salt, N-oxide, ester, quaternary ammonium salt or prodrugthereof; or D) the compound of formula III (EM-652) or formula IV(EM-800) below:

or an optical or geometric isomer thereof; or a pharmaceuticallyacceptable salt, N-oxide, ester, quaternary ammonium salt or prodrugthereof.
 6. A kit for use by a consumer to treat cancer of the liver,ovarian cancer, a desmoid tumor, glioma, pancreatic cancer, or renalcell carcinoma, the kit comprising: (a) a pharmaceutical compositioncomprising an estrogen agonist/antagonist that is compound of formula(I):

wherein: A is selected from CH₂ and NR; B, D and E are independentlyselected from CH and N; Y is (a) phenyl, optionally substituted with 1-3substituents independently selected from R⁴; (b) naphthyl, optionallysubstituted with 1-3 substituents independently selected from R⁴; (c)C₃-C₈ cycloalkyl, optionally substituted with 1-2 substituentsindependently selected from R⁴; (d) C₃-C₈ cycloalkenyl, optionallysubstituted with 1-2 substituents independently selected from R⁴; (e) afive membered heterocycle containing up to two heteroatoms selected fromthe group consisting of —O—, —NR²— and —S(O)_(n)— optionally substitutedwith 1-3 substituents independently selected from R⁴; (f) a six memberedheterocycle containing up to two heteroatoms selected from the groupconsisting of —O—, —NR²— and —S(O)_(n)— optionally substituted with 1-3substituents independently selected from R⁴; or (g) a bicyclic ringsystem consisting of a five or six membered heterocyclic ring fused to aphenyl ring, said heterocyclic ring containing up to two heteroatomsselected from the group consisting of —O—, —NR²— and —S(O)_(n)—,optionally substituted with 1-3 substituents independently selected fromR⁴; Z¹ is (a) —(CH₂)_(p) W(CH₂)_(q)—; (b) —O(CH₂)_(p) CR⁵R⁶—; (c)—O(CH₂)_(p)W(CH₂)_(q)—; (d) —OCHR²CHR³; or (e) —SCHR²CHR³—; G is (a)—NR⁷R⁸;

wherein n is 0, 1 or 2; m is 1, 2 or 3; Z² is —NH—, —O—, —S—, or —CH₂—;optionally fused on adjacent carbon atoms with one or two phenyl ringsand, optionally independently substituted on carbon with one to threesubstituents and, optionally, independently on nitrogen with achemically suitable substituent selected from R⁴; or (c) a bicyclicamine containing five to twelve carbon atoms, either bridged or fusedand optionally substituted with 1-3 substituents independently selectedfrom R⁴; or Z¹ and G in combination may be

W is (a) —CH₂—; (b) —CH═CH—; (c) —O—; (d) —NR²; (e) —S(O)_(n)—;

(g) —CR²(OH)—; (h) —CONR²—; (i) —NR²CO—;

(k) —C≡C—; R is hydrogen or C₁-C₆ alkyl; R² and R³ are independently (a)hydrogen; or (b) C₁-C₄ alkyl; R⁴ is (a) hydrogen; (b) halogen; (c) C₁-C₆alkyl; (d) C₁-C₄ alkoxy; (e) C₁-C₄ acyloxy; (f) C₁-C₄ alkylthio; (g)C₀-C₄ alkylsulfinyl; (h) C₁-C₄ alkylsulfonyl; (i) hydroxy (C₁-C₄)alkyl;(j) aryl (C₁-C₄)alkyl; (k) —CO₂H; (l) —CN; (m) —CONHOR; (n) —SO₂NHR;(o)—NH₂; (p) C₁-C₄ alkylamino; (q) C₁-C₄ dialkylamino; (r) —NHSO₂R; (s)—NO₂; (t) -aryl; or (u) —OH; R⁵ and R⁶ are independently C₁-C₈ alkyl ortogether form a C₃-C₁₀ carbocyclic ring; R⁷ and R⁸ are independently (a)phenyl; (b) a C₃-C₁₀ carbocyclic ring, saturated or unsaturated; (c) aC₃-C₁₀ heterocyclic ring containing up to two heteroatoms, selected from—O—, —N— and —S—; (d) H; (e) C₁-C₆ alkyl; or (f) form a 3 to 8 memberednitrogen containing ring with R⁵ or R⁶; R⁷ and R⁸ in either linear orring form may optionally be substituted with up to three substituentsindependently selected from C₁-C₆ alkyl, halogen, alkoxy, hydroxy andcarboxy; a ring formed by R⁷ and R⁸ may be optionally fused to a phenylring; e is 0, 1 or 2; m is 1, 2 or 3; n is 0, 1 or 2; p is 0, 1, 2 or 3;q is 0, 1, 2 or 3; or an optical or geometric isomer thereof; or apharmaceutically acceptable salt, N-oxide, ester, quaternary ammoniumsalt or prodrug thereof; and (b) instructions describing a method ofusing the pharmaceutical composition to treat cancer of the liver,ovarian cancer, a desmoid tumor, glioma, pancreatic cancer, or renalcell carcinoma.
 7. The kit of claim 6 wherein the estrogenagonist/antagonist is a compound of formula (IA):

wherein G is

R⁴ is H, OH, F, or Cl; and B and E are independently selected from CHand N or an optical or geometric isomer thereof; or a pharmaceuticallyacceptable salt, N-oxide, ester, quaternary ammonium salt, or a prodrugthereof.
 8. The kit of claim 6 wherein the estrogen agonist/antagonistis(−)-cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-olor an optical or geometric isomer thereof; or a pharmaceuticallyacceptable salt, N-oxide, ester, quaternary ammonium salt, or a prodrugthereof.
 9. The kit of claim 6 wherein the estrogen agonist/antagonistis(−)-cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol,D-tartrate salt.
 10. A kit for use by a consumer to treat cancer of theliver, ovarian cancer, a desmoid tumor, glioma, pancreatic cancer, orrenal cell carcinoma, the kit comprising: (a) a pharmaceuticalcomposition comprising an estrogen agonist/antagonist compound selectedfrom: A) 4-hydroxy tamoxifen, droloxifene, toremifene, centchroman,idoxifene, raloxifene,6-(4-hydroxy-phenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-naphthalen-2-ol,{4-[2-(2-aza-bicyclo[2.2.1]hept-2-yl)-ethoxy]-phenyl}-[6-hydroxy-2-(4-hydroxy-phenyl)-benzo[b]thiophen-3-yl]-methanone,EM-652, EM-800, GW 5638, GW 7604, or an optical or geometric isomerthereof; pharmaceutically acceptable salt, N-oxide, ester, quaternaryammonium salt, or prodrug thereof; B) a compound of formula V or VI:

wherein: R_(1B) is selected from H, OH, —O—C(O)—C₁-C₁₂ alkyl (straightchain or branched), —O—C₁-C₁₂ alkyl (straight chain or branched orcyclic), or halogens or C₁-C₄ halogenated ethers; R_(2B), R_(3B),R_(4B), R_(5B), and R_(6B) are independently selected from H, OH,—O—C(O)—C₁-C₁₂ (straight chain or branched), —O—C₁-C₁₂ (straight chainor branched or cyclic), halogens, or C₁-C₄ halogenated ethers, cyano,C₁-C₆ alkyl (straight chain or branched), or trifluoromethyl; X_(A) isselected from H, C₁-C₆ alkyl, cyano, nitro, trifluoromethyl, andhalogen; s is 2 or 3; Y_(A) is the moiety:

wherein: a) R_(7B) and R_(8B) are independently selected from the groupof H, C₁-C₆ alkyl, or phenyl optionally substituted by CN, C₁-C₆ alkyl(straight chain or branched), C₁-C₆ alkoxy (straight chain or branched),halogen, —OH, —CF₃, or —OCF₃; or b) R_(7B) and R_(8B) are concatenatedto form a five-membered saturated heterocycle containing one nitrogenheteroatom, the heterocycle being optionally substituted with 1-3substituents independently selected from the group consisting ofhydrogen, hydroxyl, halo, C₁-C₄ alkyl, trihalomethyl, C₁-C₄ alkoxy,trihalomethoxy, C₁-C₄ acyloxy, C₁-C₄ alkylthio, C₁-C₄ alkylsulfinyl,C₁-C₄ alkylsulfonyl, hydroxy (C₁-C₄)alkyl, —CO₂H, —CN, —CONHR_(1B),—NH₂, —NH(C₁-C₄ alkyl), —N(C₁-C₄ alkyl)₂, —NHSO₂R_(1B), —NHCOR_(1B),—NO₂, or phenyl optionally substituted with 1-3 (C₁-C₄)alkyl; or c)R_(7B) and R_(8B) are concatenated to form a six-membered saturatedheterocycle containing one nitrogen heteroatom, the heterocycle beingoptionally substituted with 1-3 substituents independently selected fromthe group consisting of hydrogen, hydroxyl, halo, C₁-C₄ alkyl,trihalomethyl, C₁-C₄ alkoxy, trihalomethoxy, C₁-C₄ acyloxy, C₁-C₄alkylthio, C₁-C₄alkylsulfinyl, C₁-C₄ alkylsulfonyl, hydroxy(C₁-C₄)alkyl, —CO₂H, —CN, —CONHR_(1B), —NH₂, —NH(C₁-C₄ alkyl), —N(C₁-C₄alkyl)₂, —NHSO₂R_(1B), —NHCOR_(1B), —NO₂, or phenyl optionallysubstituted with 1-3 (C₁-C₄)alkyl; or d) R_(7B) and R_(8B) areconcatenated to form a seven-membered saturated heterocycle containingone nitrogen heteroatom, the heterocycle being optionally substitutedwith 1-3 substituents independently selected from the group consistingof hydrogen, hydroxyl, halo, C₁-C₄ alkyl, trihalomethyl, C₁-C₄ alkoxy,trihalomethoxy, C₁-C₄ acyloxy, C₁-C₄ alkylthio, C₁-C₄ alkylsulfinyl,C₁-C₄ alkylsulfonyl, hydroxy (C₁-C₄)alkyl, —CO₂H, —CN, —CONHR_(1B),—NH₂, —NH(C₁-C₄ alkyl), —N(C₁-C₄ alkyl)₂, —NHSO₂R_(1B), —NHCOR_(1B),—NO₂, or phenyl optionally substituted with 1-3 (C₁-C₄)alkyl; or e)R_(7B) and R_(8B) are concatenated to form an eight-membered saturatedheterocycle containing one nitrogen heteroatom, the heterocycle beingoptionally substituted with 1-3 substituents independently selected fromthe group consisting of hydrogen, hydroxyl, halo, C₁-C₄ alkyl,trihalomethyl, C₁-C₄ alkoxy, trihalomethoxy, C₁-C₄ acyloxy, C₁-C₄alkylthio, C₁-C₄ alkylsulfinyl, C₁-C₄ alkylsulfonyl, hydroxy(C₁-C₄)alkyl, —CO₂H, —CN, —CONHR_(1B), —NH₂, —NH(C₁-C₄ alkyl), —N(C₁-C₄alkyl)₂, —NHSO₂R_(1B), —NHCOR_(1B), —NO₂, or phenyl optionallysubstituted with 1-3 (C₁-C₄)alkyl; or f) R_(7B) and R_(8B) areconcatenated to form a saturated bicyclic heterocycle containing from6-12 carbon atoms either bridged or fused and containing one nitrogenheteroatom, the heterocycle being optionally substituted with 1-3substituents independently selected from the group consisting ofhydrogen, hydroxyl, halo, C₁-C₄ alkyl, trihalomethyl, C₁-C₄ alkoxy,trihalomethoxy, C₁-C₄ acyloxy, C₁-C₄ alkylthio, C₁-C₄ alkylsulfinyl,C₁-C₄ alkylsulfonyl, hydroxy (C₁-C₄)alkyl, —CO₂H, —CN, —CONHR_(1B),—NH₂, —NH(C₁-C₄ alkyl), —N(C₁-C₄ alkyl)₂, —NHSO₂R_(1B), —NHCOR_(1B),—NO₂, or phenyl optionally substituted with 1-3 (C₁-C₄) alkyl; or anoptical or geometric isomer thereof; or a pharmaceutically acceptablesalt, N-oxide, ester, quaternary ammonium salt or prodrug thereof; C)the compound of formula Va (TSE-424) below:

or an optical or geometric isomer thereof; or a pharmaceuticallyacceptable salt, N-oxide, ester, quaternary ammonium salt or prodrugthereof; or D) the compound of formula III (EM-652) or formula IV(EM-800) below:

or an optical or geometric isomer thereof; or a pharmaceuticallyacceptable salt, N-oxide, ester, quaternary ammonium salt or prodrugthereof; and (b) instructions describing a method of using thepharmaceutical composition to treat cancer of the liver, ovarian cancer,a desmoid tumor, glioma, pancreatic cancer, or renal cell carcinoma. 11.The kit of claim 6 wherein the kit further comprises an additionalcompound that is useful to treat cancer of the liver, ovarian cancer, adesmoid tumor, glioma, pancreatic cancer, or renal cell carcinoma.